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I. SYNTHESIS OF FLUORESCENT CONJUGATES OF RISEDRONATE AND
RELATED ANALOGUES FOR BONE IMAGING.
II. SYNTHESIS OF A NOVEL BISPHOSPHONIC ACID ALKENE MONOMER.
by
Joy Lynn Fabile Bala
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
August 2009
Copyright 2009 Joy Lynn Fabile Bala
Object Description
| Title | Synthesis of fluorescent conjugates of risedronate and related analogues for bone imaging |
| Author | Bala, Joy Lynn Fabile |
| Author email | joylynnb@usc.edu; joylynnbala@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Chemistry |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2009-06-30 |
| Date submitted | 2009 |
| Restricted until | Unrestricted |
| Date published | 2009-08-03 |
| Advisor (committee chair) | McKenna, Charles E. |
| Advisor (committee member) |
Qin, Peter Haworth, Ian |
| Abstract | Bisphosphonates are structural analogues of pyrophosphate with increased hydrolytic stability. The P-C-P backbone of BPs gives rise to two additional side chains, which can be “tuned” to alter the BP’s characteristics. The ionizable phosphonate groups chelate metal ions, such as Ca2+, giving BPs exceptional bone affinity. Thus, BPs have been used for several applications due to their bone-targeting efficiency.; Nitrogen-containing bisphosphonates (N-BPs) are potent anti-resorptive agents clinically used for the treatment of various metabolic bone diseases associated with excessive bone resorption. N-BPs, such as risedronate (RIS), inhibit farnesyl diphosphate synthase (FPPS), impairing the prenylation of small GTPase proteins and inducing apoptosis of osteoclasts. N-BPs and their phosphonocarboxylate (PC) analogues have also shown promising anti-tumor effects. However, the exact mechanism by which these promising anti-cancer drugs exert their effects remain unknown. Their cellular and skeletal distributions are also relatively unclear. Therefore, specific imaging probes to elucidate these properties of BP drugs are highly desirable.; A coupling reaction was identified that introduces a universal linker group to RIS and its related analogues, 3-PEHPC (where a phosphonate is replaced by a carboxylate) and desoxyRIS (where α–OH is replaced by α-H), in a mild (aqueous, pH near neutral, 40-50 °C) synthetic step, giving high yields and regioselectivity. The key linker includes a primary amine necessary for direct acylation by an activated ester of an fluorophore, leading to the first syntheses of fluorescent and near-IR analogues of RIS. The BP imaging probes have been visualized in vitro and in vivo and continue to be critical tools for investigating these drugs.; Self-etching enamel-dentin adhesives, based on polymerizable, strongly acidic monomers, are crucial to modern dentistry but are limited by their technique sensitivity and inadequate storage stability at ambient temperature. The introduction of hydrolytically stable bonds between the polymerizable group and a strongly acidic group are believed to improve stability. Thus, polymerizable BP derivatives appear to be promising targets. The synthesis of a novel α-fluorinated, polymerizable bisphosphonic acid, [1-fluoro-1-phosphono-7-(prop-2-enamido)heptyl]phosphonic acid, was accomplished to achieve a compound that includes the following ideal characteristics: enhanced acidity, increased hydrophobicity, and improved hydrolytic stability. |
| Keyword | bisphosphonate |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m2452 |
| Rights | Bala, Joy Lynn Fabile |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Bala-3104 |
| Archival file | uscthesesreloadpub_Volume14/etd-Bala-3104.pdf |
Description
| Title | Page 1 |
| Full text | I. SYNTHESIS OF FLUORESCENT CONJUGATES OF RISEDRONATE AND RELATED ANALOGUES FOR BONE IMAGING. II. SYNTHESIS OF A NOVEL BISPHOSPHONIC ACID ALKENE MONOMER. by Joy Lynn Fabile Bala A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (CHEMISTRY) August 2009 Copyright 2009 Joy Lynn Fabile Bala |
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